Although there have been advances in ways of how to overcome tumor related immunosuppression, many factors, such as T cell lymphopenia, T cell dysfunction, disproportionately high numbers of circulating suppressive regulatory T-lymphocytes, tumor cell expression of PD-L1, and a suppressive tumor-associated macrophage (TAM) orientation, as well as impaired immune effector trafficking across the BBB, present challenges for effective immunotherapy in glioblastoma. Our basic and translational research focuses on the immunologic interactions between brain tumors, the local tissue microenvironment, and the systemic immune response. We aim to enhance immune therapies by 1) improving lymphocyte function and 2) making the tumor more susceptible to immune attack. We are interrogating components of the tumor microenvironment, such as immune modulating cells, hypoxia, and metabolic factors for their impact on immune function. We are also examining the mechanisms of immune depletion induced by corticosteroids and anti-cancer therapies. Finally, we are examining the epigenetic and molecular mechanisms employed by tumor cells to evade immune attack. The Immunology Program has two major components: Immunologic monitoring for immune-based brain tumor clinical trials and elucidating the mechanisms of immunosuppression in brain tumor patients focusing on iatrogenic causes such as corticosteroid use, lack of neoantigens and the impact of the tumor microenvironment. The immunologic monitoring will be performed as correlative biology for seminal brain tumor clinical trials, whereas the modulation of the immunosuppression in brain tumors will serve as the foundation for future, hypothesis-based clinical trials. In collaborate with NOB PTRF and Clinical Center, we are further investigating the experimental immunotherapeutics in vivo. Two clinical trials are then open recently (17C0102 Immune Checkpoint Inhibitor Nivolumab in People With Select Rare CNS Cancers; and 17C0034 Phase II trial of Radiation Therapy plus Temozolomide and Pembrolizumab with and without SPPC-6 in newly diagnosed Glioblastoma).